Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure

El‐Armouche, Ali; Pohlmann, Lutz; Schlossarek, Saskia; Starbatty, Jutta; Yeh, Yung‐Hsin; Nattel, Stanley; Dobrev, Dobromir; Eschenhagen, Thomas; Carrier, Lucie

doi:10.1016/j.yjmcc.2007.05.003

Cited by 150 publications

(139 citation statements)

References 44 publications

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“…Whereas PKA phosphorylation of RyR2 is often elevated, reduced phosphorylation levels of PLN (27), cardiac myosin-binding protein C, and troponin I have been reported in failing hearts (28). In the case of dystrophic hearts, Williams et al (5) reported a reduction in PKA phosphorylation of S16 on PLN in mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Sarma

Li²,

Oort³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant intracellular Ca 2+ regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR Ca 2+ leak in the mdx mouse model of Duchenne muscular dystrophy. mdx mice were crossed with RyR2-S2808A mice, in which PKA phosphorylation site S2808 on RyR2 is inactivated by alanine substitution. Compared with mdx mice that developed age-dependent heart failure, mdx-S2808A mice exhibited improved fractional shortening and reduced cardiac dilation. Whereas application of isoproterenol severely depressed cardiac contractility and caused 95% mortality in mdx mice, contractility was preserved with only 19% mortality in mdx-S2808A mice. SR Ca 2+ leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca 2+ release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca 2+ leak and attenuated cardiomyopathy in mdx mice, suggesting that enhanced PKA phosphorylation of RyR2 at S2808 contributes to abnormal Ca 2+ homeostasis associated with dystrophic cardiomyopathy.calcium | cardiomyopathy | dystrophin | ryanodine receptor | sarcoplasmic reticulum

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Section: Discussionmentioning

confidence: 99%

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Sarma

Li²,

Oort³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…However, this region certainly would be available for binding interactions in phosphorylated cMyBP-C. Thus, this single α-helical binding strut is especially relevant to both physiological and pathophysiological states, because the level of phosphorylation is typically high in healthy donor hearts and low in failing myocardium (30). Further, how [Ca 2+ ] in would affect MyBP-C motif structural dynamics is not known, because PKA influences contractility at submaximal but not maximal levels of Ca 2+ activation (31).…”

Section: Phosphorylation Unmasks the Charged Binding Strut Of The Trimentioning

confidence: 99%

“…Because cMyBP-C is likely to be highly phosphorylated under resting physiological conditions in healthy humans and studied mouse models of human heart disease, this uncovered helix may be an important binding region critical to normal cardiac function (26,28,32,33) and would certainly be the dominant cMyBP-C site during β-adrenergic stimulation with high phosphorylation levels, as occurs with the fight-or-flight acute stress response. Furthermore, because cMyBP-C phosphorylation decreases in patients with heart failure and hypertrophic cardiomyopathy (30,32,34), the loss of this exposed binding site could have markedly detrimental effects on the contractility response in failing hearts.…”

Section: Allosteric and Propagating Effects Of Cmybp-c Phosphorylatiomentioning

confidence: 99%

Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics

Colson

Thompson

Espinoza-Fonseca

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We have used the site-directed spectroscopies of time-resolved fluorescence resonance energy transfer (TR-FRET) and double electronelectron resonance (DEER), combined with complementary molecular dynamics (MD) simulations, to resolve the structure and dynamics of cardiac myosin-binding protein C (cMyBP-C), focusing on the N-terminal region. The results have implications for the role of this protein in myocardial contraction, with particular relevance to β-adrenergic signaling, heart failure, and hypertrophic cardiomyopathy. N-terminal cMyBP-C domains C0-C2 (C0C2) contain binding regions for potential interactions with both thick and thin filaments. Phosphorylation by PKA in the MyBP-C motif regulates these binding interactions. Our spectroscopic assays detect distances between pairs of site-directed probes on cMyBP-C. We engineered intramolecular pairs of labeling sites within cMyBP-C to measure, with high resolution, the distance and disorder in the protein's flexible regions using TR-FRET and DEER. Phosphorylation reduced the level of molecular disorder and the distribution of C0C2 intramolecular distances became more compact, with probes flanking either the motif between C1 and C2 or the Pro/Ala-rich linker (PAL) between C0 and C1. Further insight was obtained from microsecond MD simulations, which revealed a large structural change in the disordered motif region in which phosphorylation unmasks the surface of a series of residues on a stable α-helix within the motif with high potential as a protein-protein interaction site. These experimental and computational findings elucidate structural transitions in the flexible and dynamic portions of cMyBP-C, providing previously unidentified molecular insight into the modulatory role of this protein in cardiac muscle contractility. muscle | protein kinase A | fluorescence resonance energy transfer | DEER | molecular dynamics simulation

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“…cMyBP-C is extensively phosphorylated under basal conditions (22). However, the level of cMyBP-C phosphorylation decreases in animal models during injury-reperfusion injury (22), pathologic hypertrophy (22), and myocardial stunning (23,24), atrial fibrillation (25), and heart failure (26). In vitro studies demonstrated that phosphorylated cMyBP-C displays a weakened interaction with the S2 region of myosin and that this state promotes myosin-actin interaction, activating cross-bridge cycling rates (9).…”

Section: Cardiac Myosin-binding Protein-c (Cmybp-c)mentioning

confidence: 99%

Structural Insight into Unique Cardiac Myosin-binding Protein-C Motif

Howarth

Ramisetti

Nolan

et al. 2012

Journal of Biological Chemistry

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Background: Cardiac myosin-binding protein-C is a sarcomeric assembly protein necessary for the regulation of sarcomere structure and function. Results: The cMyBP-C motif is composed of two subdomains, a largely disordered N-terminal portion and a more ordered C-terminal subdomain. Conclusion: The C-terminal subdomain is capable of forming a three-helix bundle. Significance: The three-helix bundle may provide a platform for actin binding.

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Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure

Cited by 150 publications

References 44 publications

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics

Structural Insight into Unique Cardiac Myosin-binding Protein-C Motif

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